1. Field of the Invention
This invention relates in general to compositions and methods to assist humans in falling asleep and staying asleep for a normal period, and more particularly to such a composition that is consistently effective over long-term use at relatively low dosages and which has minimal side effects.
2. Background of the Invention
Sleep maladies such as insomnia are common in human beings, have serious consequences by themselves, and can lead to numerous other medical problems, even death. The consequences range from irritability, which destroys relationships and business through lowered performance and loss of the ability to function, to sickness associated with lowered resistance, such as pneumonia.
Inability to sleep is a complex phenomenon having causes as simple as the inability to put the day's events out of mind to changing metabolism and diet. Though it has been the subject of intensive study and research, it Is not yet fully understood.
The seriousness of sleep malfunction is such that innumerable remedies and methods have been created to deal with the problem. See Treisman et al., “Insomnia,” Johns Hopkins POC-IT Center, 12 Jun. 2010 (online) pp. 1-3, which discusses insomnia treatment for HIV patients and gives recommendations for initial dosages of a variety of medications. Examples of sleep medications include over-the-counter medicines such as Tylenol PM®, compositions containing melatonin, herbal remedies, as well as pharmaceuticals such as zolpidem, quetiapine, and many others. It also includes sleep-inducing processes such as sleep-inducing music and videos. Sleep malfunction is so dehabiliting to those to whom it occurs that they often will blindly grab at any composition or process that promises relief. While some of these are effective, tolerance generally develops for most medications requiring increasingly higher dosages. There as yet does not exist a sleep assist composition or method that is effective, does not have significant undesirable side effects, and does not require increasingly higher dosages to remain effective. The very proliferation of sleep remedies is a testament to both the seriousness of the problem and the lack of a suitable solution to the problem.
Zolpidem, mentioned above, for some time was widely prescribed by physicians. However, like many other sleep medications, the body develops tolerance for the drug, and larger and larger dosages are required for it to remain effective. The tolerance can develop after just a few weeks of use. Moreover, zolpidem becomes addictive if taken for an extended period of time, i.e., about two months or longer, due to drug tolerance and physical dependence. C. K. Kirkwood, “Management of Insomnia”, J. Am. Pharm. Assoc. (Wash) 1999 September-October: 39(5) 688-696; and Mariani et al., “Quetiapine Treatment of Zolpidem Dependence,” American Journal in Addictions, 2007 (16 Apr. 2009-online), Vol. 16, Issue 5, p. 426. Sleep becomes impossible without it. Further, it is effective for only about four hours, after which the user usually wakes up. Thus, it is now available in an extended release formulation. However, the extended release formulation makes it difficult to wake up and function properly if there becomes a need to wake up after the medicine has been taken, such as the user's child that needs assistance or some other emergency. Further, it still has the problems that one becomes dependent on it for sleep and, as time goes on, ever larger doses are required for effectiveness. Other sleep medications can be substituted for zolpidem to break the dependence, but tolerance also develops for these substitutes. See Mariani et al., supra. Quetiapine is approved for psychic uses and is not approved for sale as a sleep medication, but physicians often prescribe it for sleep. In the Mariani et al. report, the development of tolerance for the quetiapine ultimately required dosages of 800 mg. Moreover, quetiapine does not enter the system for about an hour or more after being ingested. Thus, if the user forgets to take it until the user is ready to sleep, the result is an extended period of wakefulness. This wakefulness can lead to restlessness that prevents the drug from taking effect. While quetiapine tends to keep the user asleep longer than zolpidem, it still does not provide a full eight hours of sleep unless it is taken in a large enough dosage that creates drowsiness into the working day. In fact, the recommended amounts of quetiapine generally result in the side effect of somnolence (drowsiness). See Wikipedia, Quetiapine: Adverse Effects and astrazeneca-us.com at /pi/Seroquel.pdf at Adverse Reactions.
Zolpidem and quetiapine are both mentioned in a number of patent applications. See United States Published Patent Application No. US 2008/0064671 A1 (hereinafter “the '671 Application”) published Mar. 13, 2008, in the names of Carrolee Barlow, Todd A. Carter, Andrew Morse, Kal Trenner, and Kym L. Lorrain and assigned to BrainCells, Inc.; United States Published Patent Application No. US 2008/0103165 A1 (hereinafter “the '165 Application”) published May 1, 2008, in the names of the same inventors as the '671 Application and assigned to BrainCells, Inc.; United States Published Patent Application No. US 2008/0103105 A1 (hereinafter “the '105 Application”) published May 1, 2008, in the names of the same inventors as the '671 Application and assigned to BrainCells, Inc.; United States Published Patent Application No. US 2008/0108574 A1 (hereinafter “the '574 Application”) published May 8, 2008, in the names of the same inventors as the '671 Application and assigned to BrainCells, Inc.; United States Published Patent Application No. US 2008/0167291 A1 (hereinafter “the '291 Application”) published Jul. 10, 2008, in the names of the same inventors as the '671 application and assigned to BrainCells, Inc. (all of the foregoing referred to together as “the BrainCells Applications”). The '671 Application discloses the use of a 4-acylaminopyridine derivative in combination with one or more other neurogenic agents for more than a hundred different human disorders which include sleep disorders (see [0082]). Several thousand different neurogenic agents are mentioned that can be used in combination with the 4-acylaminopyridine derivative. In some embodiments, a reported anti-psychotic agent is used in combination with the 4-acylaminopyridine derivative. One anti-psychotic agent mentioned is quetiapine ([0131]). In other embodiments, a GABA-A modulator is the neurogenic agent ([0203]). Many hundreds of possible GABA-A modulators are mentioned ([203]-[207]), including zolpidem ([0206]). The reference never mentions that quetiapine and zolpidem should be used together. The other BrainCells Applications all have essentially the same disclosure as the '671 application, except that the agent that is the key ingredient in the combinations is different. Again, quetiapine and zolpidem are mentioned only as one part of the disclosed combination in different ones of many thousands of possible embodiments; and it is never suggested that they be used together.
United States Published Patent Application No. US 2005/0233010 A1 (hereinafter “Satow”) published Oct. 20, 2005, in the name of Phillip Maxwell Satow discloses a therapy that administers a lithium salt together with another pharmaceutically active agent (see [0026]). In certain embodiments, the lithium is co-administered with a sedative-hypnotic drug, one of which is zolpidem (see [0031]). In another aspect of the invention, a patient suffering from anxiety, depression, or a psychotic disorder is treated by co-administering lithium carbonate together with an atypical antipsychotic, one of which is quetiapine (see [0047]). It is not disclosed that zolpidem and quetiapine are combined.
United States Published Patent Application No. US 2009/0035370 (hereinafter “Bortz et al.”) published Feb. 5, 2009, in the names of Jonathan David Bortz and Michael Norman Grimshaw discloses a quetiapine therapy that administers a major quetiapine component in an immediate release form and a minor quetiapine component in an extended release, delayed extended release, or delayed pulsed release form (see [0018]-[0020]). For a sleep disorder, the daily dosage of quetiapine is about 50 to 300 mg. Dosages lower than this range may be administered at the beginning of a treatment period (see [0045]). Optionally, the quetiapine is administered together with an additional pharmaceutical agent. The pharmaceutical agent may be any pharmaceutical agent appropriate to the condition (see [0124]). In one embodiment, the quetiapine is administered together with a sleep aid, which may be zolpidem (see [0125] and [0130]). No advantages for zolpidem over other sleep aids are disclosed, and no dosages for zolpidem are disclosed. In fact, zolpidem is mentioned as only one of approximately ninety-four other “additional pharmaceutical agents” that can be used in combination with quetiapine. Thus, this reference in fact makes it more difficult for one skilled in the art to solve the issues with quetiapine than if the reference did not exist, as it would require a huge multitude of experiments to distinguish which of the ninety-four agents would be useful and in what dosage.
Other sleep potions either do not work well, have serious side effects, or both. For example, while over-the-counter medications work on some, they do not work for all, and usually do not continue to work over extended periods. Further, in higher doses, most become a stimulant. Thus, if the user does not fall asleep immediately, the user may take an additional dose and not be able to sleep at all.
For the above reasons, there remains a significant need for a sleep composition and method that is safe and effective, particularly over extended periods, and does not have significant side effects.